K+ currents responsible for repolarization in mouse ventricle and their modulation by FK-506 and rapamycin

Modulation of mouse ventricular action potentials and K+ currents was exami ned using the whole cell patch-clamp technique. The composite mouse ventric ular K+ current (consisted of an outward transient followed by a slowly dec aying sustained component. Use of the K+ channel blockers tetraethylammoniu m and 4-aminopyridine and a transgenic mouse model revealed three pharmacol ogically and kinetically distinct currents: I-to, which contributed to the transient component; I-K, which contributed to the sustained component; and a slowly activating current (I-slow), which contributed to both components . The immunosuppressant FK-506 increased action potential duration at 90% r epolarization by 66.7% by decreasing the sustained component (-48% at +60 m V) and prolonging recovery from inactivation (by 26% at 200 ms) of the tran sient component. These effects were isolated to I-K and I-to, respectively. Rapamycin had strikingly similar effects on these currents. Both FK-506 an d rapamycin are known to target the immunophilin FKBP12. Thus we conclude t hat FKBP12 modulates specific mouse K+ channels, and thus the mouse ventric ular action potential, by interacting directly with K+ channel proteins or with other associated regulatory proteins.